Ferulic acid ameliorates high-fat diet-induced hyperlipidemia in mice via suppressing the PGC-1β/miR-378a-3p axis.

Hyperlipidemia (HLP) has emerged as a prevalent chronic metabolic disorder and seriously threatens human health. Given the limitations of current pharmacotherapies, the exploration of safe and effective natural bioactive compounds for HLP management has become an urgent research priority. Ferulic acid (FA), a common dietary phenolic compound, exhibits significant lipid-lowering effects. This study investigates the underlying molecular mechanisms of FA in HLP. It was found that FA supplementation significantly alleviated HLP phenotypes in a dose-dependent manner, without inducing obvious toxic side effects on major organs. In vitro, FA effectively suppressed free fatty acid-induced lipid accumulation in hepatocytes. Mechanistically, FA significantly downregulated the expression of miR-378a-3p, a well-characterized HLP-associated microRNA. The reduced miR-378a-3p further inhibited very low-density lipoprotein secretion and activated fatty acid oxidation, contributing to the lipid-lowering effects of FA. Importantly, we identified that FA inhibited miR-378a-3p expression by suppressing the peroxisome proliferator-activated receptor (PPAR) gamma-coactivator-1beta/liver X receptor α axis. Collectively, this study uncovered a potential regulatory pathway through which FA ameliorates HLP, providing experimental evidence for FA as a potential natural dietary supplement for the prevention and management of HLP.